Impact of Somatic Mutations on Treatment Response and Resistance in Chronic Myeloid Leukemia.

Abstract

Introduction: Tyrosine kinase inhibitors (TKIs) have transformed the treatment of chronic myeloid leukemia (CML); yet, diverse molecular responses and resistance persist. BCR::ABL1 kinase-domain (TKD) mutations constitute just a fraction of this resistance, and the impact of additional somatic mutations on disease progression and early molecular response remains incompletely defined.

Methods: This single-centre cohort study analyzed 109 NGS-tested patients with CML, comprising 44 with TKI-resistant disease and 65 newly diagnosed patients. Targeted next-generation sequencing using a 135-gene myeloid panel was performed on 109 patients. An additional pilot subgroup of 30 TKI-resistant patients underwent BCR::ABL1 kinase-domain analysis by PCR/Sanger sequencing and was analyzed separately. Molecular response was assessed using BCR::ABL1 transcript levels on the International Scale and interpreted according to ELN 2020 recommendations.

Results: Somatic mutations were identified in 52.3% of TKI-resistant and 29.2% of newly diagnosed patients. All Cohort 1 blast-crisis patients were mutation-positive, and several concurrent abnormalities were more common in Cohort 1 than in Cohort 2, indicating clonal complexity. In Cohort 2, MMR was achieved in 28/39 (71.8%) mutation-negative and 6/13 (46.2%) mutation-positive patients. Mutation-positivity at baseline was associated with reduced MMR chances but not statistically significant (odds ratio 0.34; 95% confidence interval 0.09-1.23; p = 0.099). ASXL1 emerged as the most common non-ABL1 mutation but was not statistically significant.

Conclusions: In this Indian CML cohort, somatic mutations were prevalent in TKI-resistant disease, linked to advanced phase and clonal complexity, and demonstrated a non-significant trend toward lower early MMR at diagnosis, highlighting the importance of genomic testing in this context.